HK1237332B - Chiral resolution method of n-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives - Google Patents

Description

Chiral Separation of N-[4-(1-aminoethyl)-phenyl]-sulfonamide Derivatives

Technical Field

The present disclosure relates to methods for the chiral resolution of N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives.

Background Art

Recently, the demand for stereochemically pure compounds has increased rapidly. One important use of these pure stereoisomers is as synthetic intermediates in the pharmaceutical industry. For example, it has become increasingly apparent that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages generally include fewer side effects and greater efficacy of enantiomerically pure compounds [see, for example, Stinson, S.C., ChemEng News, September 28, 1992, pp. 46-79].

For example, triadimenol can exist as four isomers. The (-)-(1S, 2R)-isomer is more active than the (+)-(1R, 2R)-isomer, and the (-)-(1S, 2S)-isomer is more active than the -(1R, 2S)-isomer. Of the four isomers of dichlorobutazole, the (1R, 2R)-isomer is known to be more active. In addition, for ethiconazole, the (+)-(2S, 4S)-isomer and the (-)-(2S, 4R)-isomer are known to have better fungicidal effects than the other isomers.

Therefore, if only one isomer with higher activity can be selectively produced, a smaller amount can be used to achieve better results, thereby reducing environmental pollution caused by the use of chemicals. Especially for pharmaceuticals, if one isomer shows toxicity in the human body, it is very important to selectively produce only one isomer.

Therefore, in the fields of medicine, pharmacy, and biochemistry, the preparation of optically pure compounds for improving drug efficacy or preventing side effects is a very important issue.

However, there are still many drugs used as racemic compounds, which have inevitable side effects due to the presence of undesirable enantiomers (see, for example, Nguyen et al., Chiral Drugs: An Overview, Int. J. Biomed. Sci., 2 (2006) 85-100). Some techniques can be used for chiral separation on a preparative or analytical scale. However, it takes a lot of time and effort to find a separation technique suitable for the racemate of interest. Even if people succeed in separating the enantiomers, they will face the next difficulty, that is, to enable chiral separation on an industrial scale.

For example, the efficacy of pure stereoisomers of vanillic acid antagonists including N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives has been described [eg, WO 2008-013414 A1, WO 2007-133637 A2, WO 2007-129188 A1, WO 2010-010934 A1].

As a method for synthesizing a single isomer of N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives, asymmetric synthesis using Ellman's reagent is known. For example, WO 2008-013414 A1, WO 2007-133637 A2, WO2007-129188 A1 and WO 2010-010934 A1 provide a method for obtaining the target stereoisomer by introducing Ellman's reagent and using this reagent to induce asymmetric reduction. However, the shortcoming of this method is that low temperature reaction conditions should be maintained to achieve high optical purity (enantiomeric excess, %ee). In addition, this method is dangerous because excessive hydrogen and heat are produced when the reaction terminates. In addition, the disposal cost of excessively produced organic and inorganic waste is also disadvantageous in economic terms.

Summary of the Invention

Technical issues

Although asymmetric synthesis of N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives has been reported, due to economic and safety issues, no commercial-scale preparation methods have been established. Therefore, the present disclosure aims to address the problems of existing asymmetric synthesis methods and provide a new method for chiral resolution of stereoisomers into S or R compounds with high optical purity.

Technical Solution

In one aspect, the present disclosure provides a method for resolving N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives of formula (I) into corresponding compounds with high optical purity by using O,O′-diacyltartaric acid derivatives (an example of a chiral auxiliary) and a soluble salt-forming acid (an example of a salt-forming compound):

In one embodiment, the present disclosure relates to a method for resolving (R,S)-N-[4-(1-aminoethyl)-phenyl]-sulfonamide to N-[4-(1-aminoethyl)-phenyl]-sulfonamide with high optical purity, which comprises: (i) mixing a (R,S)-N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative with an optically active O,O′-diacyltartaric acid derivative (an example of a chiral auxiliary) and a soluble salt-forming acid (an example of a salt-forming compound) in a polar protic solvent to prepare a (R)- or (S)-N-[4-(1-aminoethyl)]-sulfonamide diacyltartaric acid salt or a solvate thereof with high optical purity, and (ii) releasing the obtained N-[4-(1-aminoethyl)-phenyl]-sulfonamide salt or a solvate thereof with high optical purity by using a base.

According to the methods of the present disclosure, N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives can be readily resolved into corresponding compounds with high optical purity.

N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide is the common name of the compound having the following formula (II):

And it is considered to be an intermediate product that can be used to prepare a compound that is used as a TRPV1 (transient receptor potential cation channel subfamily V member 1, or capsaicin receptor or vanilloid receptor 1) antagonist.

As can be seen from formula (II), N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide is a chiral compound in which the amine group is bonded to an asymmetric carbon atom (chiral center).

Beneficial effects

According to the chiral separation method of one aspect of the present disclosure, a stereoisomer mixture, particularly a stereoisomer mixture of a compound in which an amine group is bonded to an asymmetric carbon atom, can be easily chirally separated into compounds with high optical purity. Compared with the asymmetric synthesis method using Ellman's reagent, this synthetic method provides improved safety and economy. It makes it possible to chirally separate with comparable or better optical purity, and provides improved economy and environmental friendliness through the collection and recovery of salt. Therefore, this method can be advantageously used in the field of medicine and cosmetics that require the chiral separation of compounds.

In particular, the method according to the present disclosure allows for the efficient preparation of target stereoisomers with comparable or better optical purity than existing asymmetric synthesis methods using Ellman's reagents. It is also efficient for large-scale production and provides economic advantages.

Detailed Description of the Invention

In one aspect, the present disclosure provides a method for the resolution of a mixture of stereoisomers of a compound,

It comprises the step of mixing the stereoisomer mixture of a compound with:

(i) a chiral auxiliary; and

(ii) auxiliary salt-forming compounds,

Thereby, the diastereomeric salt of the chiral auxiliary (i) and the compound is precipitated. In one aspect, the resolution method involves a chiral resolution method.

In one aspect, the present disclosure provides a process for resolving a mixture of stereoisomers of a compound of formula (I),

It comprises the step of mixing the stereoisomer mixture of the compound of formula (I) with the following substances in the presence of a solvent:

(i) a chiral auxiliary; and

(ii) auxiliary salt-forming compounds,

Thereby, the diastereomeric salt of the chiral auxiliary (i) and the compound of formula (I) is precipitated.

In one embodiment of the present disclosure, the process according to the present invention provides stereoisomers of the compound of formula (I) in enantiomeric excess, in particular with high optical purity.

The term "enantiomeric excess" in this disclosure generally includes any increase in the ratio of enantiomers, and thus includes not only enantiomeric excess compared to a racemic mixture, but also an increase of one enantiomer relative to the other compared to a mixture in which the ratio of enantiomers is not 1:1 (such as in a racemate). In some embodiments, the term enantiomeric excess specifically corresponds to an enantiomeric excess value ("% ee") of at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%.

The term "high optical purity" in this disclosure is a term well known in the art. In some embodiments, the term "high optical purity" corresponds to an enantiomeric excess ("% ee") of at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%.

In one aspect, the present disclosure provides a method for chiral resolution of a mixture of stereoisomers comprising mixing the mixture of stereoisomers with a soluble hydrochloric acid (an example of a salt-forming compound) and an optically active O,O'-diacyltartaric acid derivative (an example of a chiral auxiliary).

The term "salt-forming compound" in this disclosure refers not only to a compound that resolves a mixture of stereoisomers, but also to a compound that helps improve the optical purity of the mixture of stereoisomers. The different solubilities of salts formed with enantiomers and chiral auxiliary agents in the salt-forming compound are used to help resolve the mixture of stereoisomers. The salt-forming compound can be an acid or a salt thereof that can dissolve the mixture of stereoisomers to be resolved. This salt-forming compound helps one enantiomer that does not form an insoluble salt with the chiral auxiliary remain soluble, thereby facilitating the production of an insoluble salt of the other enantiomer in enantiomeric excess.

In an exemplary embodiment of the present disclosure, a soluble salt-forming acid (an example of a salt-forming compound) can be selected from mandelic acid, camphorsulfonic acid, stereoisomers thereof, and combinations thereof. The term "chiral auxiliary" in the present disclosure is well known to those skilled in the art, and specifically refers to a chemical compound or unit that is temporarily incorporated into an organic synthesis to control the stereochemical outcome of the synthesis. The chirality of the chiral auxiliary can bias the stereoselectivity of one or more subsequent reactions (see, for example, chiral auxiliary, Wikipedia: http://en.wikipedia.org/wiki/Chiral_auxiliary). In the present disclosure, the terms chiral auxiliary and chiral acid can be used interchangeably.

In an exemplary embodiment of the present disclosure, the chiral auxiliary agent may be an O,O'-diacyltartaric acid derivative. The chiral auxiliary agent may be selected from 2,3-dibenzoyltartaric acid, O,O'-di-p-toluoyltartaric acid, stereoisomers thereof, and combinations thereof.

In an exemplary embodiment of the present disclosure, 2,3-dibenzoyltartaric acid can be (+)-2,3-dibenzoyl-D-tartaric acid or (-)-2,3-dibenzoyl-L-tartaric acid (which are optical isomers of each other), and O,O'-di-p-toluoyltartaric acid can be (+)-O,O'-di-p-toluoyl-D-tartaric acid or (-)-O,O'-di-p-toluoyl-L-tartaric acid (which are optical isomers of each other). Although the D and L forms of tartaric acid derivatives can be used alone or in combination, it is preferred that they be used alone without mixing with each other. When the tartaric acid derivatives of D and L forms are used in combination in the method according to the present disclosure, lower optical purity can be obtained compared with when using D or L form alone.

In an exemplary embodiment of the present disclosure, mandelic acid can be D-mandelic acid or L-mandelic acid (which are optical isomers of each other), or a combination thereof, and camphorsulfonic acid can be (1R)-(-)-10-camphorsulfonic acid or (1S)-(+)-10-camphorsulfonic acid (which are optical isomers of each other), or a combination thereof. As shown in the Examples, the optical isomer form of mandelic acid or camphorsulfonic acid does not significantly affect the optical isomer form of the final product, and when any optical isomer of mandelic acid or camphorsulfonic acid is used alone or in combination, a final product of high optical purity can be obtained.

In an exemplary embodiment of the present disclosure, the stereoisomer mixture may be a stereoisomer mixture of a compound having an asymmetric carbon atom. Specifically, in an exemplary embodiment of the present disclosure, the compound having an asymmetric carbon atom may be a compound having an amine group bonded thereto. Specifically, in an exemplary embodiment of the present disclosure, in addition to the amine group, the compound may also have a substituted or unsubstituted phenyl group bonded to the asymmetric carbon atom. More specifically, in an exemplary embodiment of the present disclosure, the compound having an asymmetric carbon atom may be a compound of formula (I).

In an exemplary embodiment of the present disclosure, an R or S optical isomer can be obtained with high optical purity from a stereoisomer mixture.

In an exemplary embodiment of the present disclosure, when the chiral auxiliary is selected from the group consisting of (+)-2,3-dibenzoyl-D-tartaric acid and (+)-O,O′-di-p-toluoyl-D-tartaric acid, and combinations thereof, the R enantiomer can be obtained in high enantiomeric excess.

In an exemplary embodiment of the present disclosure, when the chiral auxiliary is selected from the group consisting of (-)-2,3-dibenzoyl-L-tartaric acid or (-)-O,O′-di-p-toluoyl-L-tartaric acid and combinations thereof, the S enantiomer can be obtained in high enantiomeric excess.

In an exemplary embodiment of the present disclosure, the salt-forming compound may be D-mandelic acid, L-mandelic acid, (1R)-(-)-10-camphorsulfonic acid, or (1S)-(+)-10-camphorsulfonic acid, or a combination thereof.

In an exemplary embodiment of the present disclosure, the compound in which the amine group is bonded to an asymmetric carbon atom may have a structure of Formula (I):

in

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are each independently any one selected from H, -NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and halogen, and

_R1 and _R2 are different from each other.

In an exemplary embodiment of the present disclosure, the halogen may be at least one selected from F, Cl, Br, and I, specifically selected from F and Cl.

In an exemplary embodiment of the present disclosure, R ₁ may be one selected from the group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group, and R ₂ may be hydrogen.

In an exemplary embodiment of the present disclosure, R ₁ may be methyl, R ₃ and R ₇ may be hydrogen, and R ₄ , R ₅ and R ₆ may each independently be one selected from F, Cl, Br, I and C _1-6 alkyl.

In an exemplary embodiment of the present disclosure, R ₄ and R ₆ may be F, and R ₅ may be methyl.

In an exemplary embodiment of the present disclosure, the compound may be N-{4-[(1R/S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide.

In an exemplary embodiment of the present disclosure, the solvent may be added in an amount to achieve complete dissolution of all reactants.

In an exemplary embodiment of the present disclosure, the solvent may be a polar protic solvent.

In an exemplary embodiment of the present disclosure, the polar protic solvent can be one or more selected from water, C _1-14 alcohols, isopropanol, acetic acid, nitromethane, propionic acid, formic acid, and combinations thereof. Specifically, the polar protic solvent can be one or more selected from water, methanol, ethanol, and isopropanol. More specifically, the polar protic solvent can be methanol or isopropanol. More specifically, the polar protic solvent can be isopropanol.

In an exemplary embodiment of the present disclosure, the polar protic solvent may be used in an amount of 5 to 15 times, specifically 7 to 13 times, more specifically 9 to 11 times, more specifically 10 times, based on the total weight of the stereoisomer mixture (i.e., volume [solvent]/weight [stereoisomer] or (volume/weight)).

In an exemplary embodiment of the present disclosure, the mixing may be performed at 40° C. to 70° C. or at the boiling point of the solvent or solvent mixture. The mixing may be performed for 1 to 4 hours. In an exemplary embodiment of the present disclosure, the mixing may be performed by stirring under reflux.

In an exemplary embodiment of the present disclosure, the mixing may be performed at a temperature of at least 30° C., at least 40° C., more specifically at least 50° C., or at the boiling point of the solvent or solvent mixture.

In an exemplary embodiment of the present disclosure, the mixing temperature may be 30° C. or higher, 40° C. or higher, 50° C. or higher, 60° C. or higher, or 70° C. or higher, or 70° C. or lower, 60° C. or lower, 50° C. or lower, 40° C. or lower, or 30° C. or lower. The mixing temperature may be specifically 40° C. to 60° C., more specifically 45° C. to 55° C., more specifically 50° C.

In an exemplary embodiment of the present disclosure, the mixing time can be 1 hour or longer, 2 hours or longer, 3 hours or longer, 4 hours or longer or 5 hours or longer, or 6 hours or shorter, 5 hours or shorter, 4 hours or shorter, 3 hours or shorter, 2 hours or shorter or 1 hour or shorter. The mixing time can specifically be 2 to 4 hours, more specifically the mixing time is 2.5 to 3.5 hours, more specifically 3 hours.

In an exemplary embodiment of the present disclosure, the method can be carried out by reacting two molar equivalents of a compound having a structure of formula (I) (comprising R and S optical isomers in a given ratio) per one molar equivalent of a chiral auxiliary. In an exemplary embodiment of the present disclosure, the reaction can be carried out according to Scheme 1.

[Scheme 1]

According to Scheme 1, two molecules of a compound of formula (I) having an optical activity bond with one molecule of a chiral auxiliary to form an insoluble salt that can precipitate. In contrast, the compound not bonded to the chiral auxiliary dissolves in the salt-forming compound and therefore does not precipitate. Through this reaction, the method according to the present disclosure can resolve compounds with high optical purity from a mixture of stereoisomers. On the other hand, if one molecule of the compound of formula (I) bonds with one molecule of a chiral auxiliary to form a salt, the chiral resolution required by the present disclosure is not as good as when the two molecules are bonded.

In an exemplary embodiment of the present disclosure, the molar equivalent of the chiral auxiliary relative to the stereoisomer mixture may be a molar equivalent for reacting two molecules of the R- or S-form compound having the structure of formula (I) with one molecule of the chiral auxiliary.

In an exemplary embodiment of the present disclosure, the molar equivalent ratio of the chiral auxiliary to one molar equivalent of the stereoisomer mixture may be equal to or less than 0.5, 0.10 to 0.5, 0.15 to 0.5, 0.25 to 0.35, or 0.25.

In an exemplary embodiment of the present disclosure, the chiral auxiliary agent may be used in an amount of 0.01 equivalent or more, 0.05 equivalent or more, 0.10 equivalent or more, 0.15 equivalent or more, 0.2 equivalent or more, 0.25 equivalent or more, 0.3 equivalent or more, 0.35 equivalent or more, 0.4 equivalent or more, 0.45 equivalent or more, 0.5 equivalent or more, 0.55 equivalent or more, or 0.6 equivalent or more, or 0.6 equivalent or less, 0.55 equivalent or less, 0.5 equivalent or less, 0.45 equivalent or less, 0.4 equivalent or less, 0.35 equivalent or less, 0.3 equivalent or less, 0.25 equivalent or less, 0.2 equivalent or less, 0.15 equivalent or less, 0.10 equivalent or less, 0.05 equivalent or less, or 0.01 equivalent or less, per 1 equivalent of the mixture of stereoisomers.

In an exemplary embodiment of the present disclosure, the molar equivalent ratio of the salt-forming compound to 1 molar equivalent of the stereoisomer mixture may be 0.50 to 1.5, 0.75 to 1.5, or 0.75 to 1.0.

Specifically, per 1 equivalent of the stereoisomer mixture, the amount of the salt-forming compound used may be 0.5 equivalent or more, 0.55 equivalent or more, 0.6 equivalent or more, 0.65 equivalent or more, 0.7 equivalent or more, 0.75 equivalent or more, 0.8 equivalent or more, 0.85 equivalent or more, 0.9 equivalent or more, 0.95 equivalent or more, 1.0 equivalent or more, 1.05 equivalent or more, 1.1 equivalent or more, 1.15 equivalent or more, 1.2 equivalent or more, 1.25 equivalent or more, 1.3 equivalent or more, 1.35 equivalent or more, 1.4 equivalent or more, 1.45 equivalent or more, 1.5 equivalent or more, 1.55 equivalent or more. or more or 1.6 equivalents or more, or 1.6 equivalents or less, 1.55 equivalents or less, 1.5 equivalents or less, 1.45 equivalents or less, 1.4 equivalents or less, 1.35 equivalents or less, 1.3 equivalents or less, 1.25 equivalents or less, 1.2 equivalents or less, 1.15 equivalents or less, 1.1 equivalents or less, 1.05 equivalents or less, 1.0 equivalents or less, 0.95 equivalents or less, 0.9 equivalents or less, 0.85 equivalents or less, 0.8 equivalents or less, 0.75 equivalents or less, 0.7 equivalents or less, 0.65 equivalents or less, 0.6 equivalents or less, 0.55 equivalents or less or 0.50 equivalents or less.

In an exemplary embodiment of the present disclosure, the molar equivalent ratio of the chiral auxiliary agent and the salt-forming compound to 1 molar equivalent of the stereoisomer mixture may be 0.6 to 2.0, 0.75 to 2.0, 0.8 to 2.0, 1.0 to 1.85, or 1.0 to 1.35. Specifically, the molar equivalent ratio of the chiral auxiliary agent and the salt-forming compound may be a value obtained by adding the molar equivalents of the chiral auxiliary agent and the molar equivalents of the salt-forming compound.

In an exemplary embodiment of the present disclosure, when a salt-forming compound and a chiral auxiliary are used in combination, higher optical purity can be obtained when the chiral auxiliary is used in a smaller equivalent ratio than that of the salt-forming compound per 1 equivalent of the racemic mixture.

In an exemplary embodiment of the present disclosure, a stereoisomer of a compound having an enantiomeric excess of at least 96%, at least 97%, at least 98%, at least 99%, or between 96% and 99% is provided by a method according to the present disclosure. In another aspect, the present disclosure provides an R or S optical isomer compound prepared by resolving a mixture of stereoisomers according to a method of the present disclosure.

In an exemplary embodiment of the present disclosure, the stereoisomer may be N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide or N-{4-[(1S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide.

In the context of this disclosure, an asymmetric carbon atom may refer to a carbon atom to which four different types of atoms, groups or functional groups are attached.Compounds with asymmetric carbon atoms exhibit optical rotation, optical activity or optical isomerism.

In the context of the present disclosure, a stereoisomer mixture may refer to a mixture of two optically active enantiomers. The mixing ratio may be 1:1 (corresponding to a racemic mixture), or more specifically, any ratio from 1:10 to 10:1. In the context of the present disclosure, a stereoisomer mixture may be an artificial synthesis of an R optical isomer and an S optical isomer in an unknown ratio or a mixture thereof. According to the method of the present disclosure, the ratio of one of the R or S optical isomers can be significantly increased, and the target optical isomer can be obtained with high optical purity, regardless of the mixing ratio of the mixture. Specifically, the stereoisomer mixture to be resolved may be a 1:1 mixture of an R optical isomer and an S optical isomer.

In the context of the present disclosure, N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide refers to a compound with a molecular weight of 250.27 Da and a CAS number of 1202743-51-8. In the present disclosure, it can be used interchangeably with INT-2. It can also be a stereoisomer mixture in which R and S optical isomers are mixed.

In the context of the present disclosure, N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide hydrochloride refers to the compound with CAS No. 956901-23-8 having a molecular weight of 286.73 Da, and N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide refers to the compound with CAS No. 957103-01-4. In the present disclosure, N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide can be used interchangeably with the R isomer of INT-3.

In the context of the present disclosure, 3-(2-propyl-6-trifluoromethylpyridin-3-yl)-acrylic acid refers to the compound with CAS number 1005174-17-3 and a molecular weight of 259.22 Da.

In the context of the present disclosure, (R)-N-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-3-(2-propyl-6-trifluoromethylpyridin-3-yl)-acrylamide (PAC-14028) refers to a compound with a molecular weight of 491.47 Da and a CAS number of 1005168-10-4.

In an exemplary embodiment of the present disclosure, the R or S optical isomer of INT-3 can be obtained by a method comprising the following steps:

Mixing INT-2 (N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide) with a chiral auxiliary and a salt-forming compound;

Adding 10 times the weight of the INT-2 to the mixture (volume/weight) of a polar protic solvent;

The resulting mixture solution is stirred with the added polar protic solvent under reflux at 30° C. to 70° C. for 1 to 4 hours;

cooling the mixture; and

The chiral acid salt of INT-3 was obtained by filtration of the resulting solid.

In an exemplary embodiment of the present disclosure, after stirring under reflux, cooling may be performed at 15°C to 30°C.

In an exemplary embodiment of the present disclosure, cooling can be carried out at a temperature of 10°C or higher, 15°C or higher, 20°C or higher, 22°C or higher, 24°C or higher, 25°C or higher, 26°C or higher, 28°C or higher, 30°C or higher or 35°C or higher, or 40°C or lower, 35°C or lower, 30°C or lower, 28°C or lower, 26°C or lower, 25°C or lower, 24°C or lower, 22°C or lower, 20°C or lower, 15°C or lower, 10°C or lower or 5°C or lower.

In an exemplary embodiment of the present disclosure, the method may further include a step of separating the chiral acid from the obtained chiral acid salt of INT-3. Specifically, the separation may be performed by the following steps: adding the chiral acid salt of INT-3 to water (5 times the weight of the chiral acid salt of INT-3) and 2 equivalents of a 28% by volume ammonia solution, stirring for 20 to 50 minutes to obtain a suspension, filtering the suspension by removing excess water under reduced pressure and obtaining the R or S optical isomer of INT-3.

In another aspect, the present disclosure provides a method for chiral resolution of a mixture of stereoisomers, comprising:

(1) A step of mixing a stereoisomer mixture of a compound in which an amine group is bonded to an asymmetric carbon atom with a chiral auxiliary and a salt-forming compound.

In an exemplary embodiment of the present disclosure, the compound may be N-{4-[(1R/S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide.

In an exemplary embodiment of the present disclosure, the chiral auxiliary agent in step (1) may be at least one selected from 2,3-dibenzoyltartaric acid, O,O'-di-p-toluoyltartaric acid, stereoisomers thereof, and combinations thereof.

In an exemplary embodiment of the present disclosure, the salt-forming compound in step (1) may be at least one selected from mandelic acid, camphorsulfonic acid, stereoisomers thereof, and combinations thereof.

In an exemplary embodiment of the present disclosure, the method may further include, after step (1), the step of (2) adding a solvent to the mixture of step (1).

In an exemplary embodiment of the present disclosure, the solvent may be a polar protic solvent.

In an exemplary embodiment of the present disclosure, the method may further include: (3) a step of stirring the obtained mixture solution under reflux.

In an exemplary embodiment of the present disclosure, the stirring in step (3) may be carried out for 30 minutes or more, 1 hour or more, 1.5 hours or more, 2 hours or more, 2.5 hours or more, 3 hours or more, 3.5 minutes or more or 4 hours or more, or 5 hours or less, 4.5 hours or less, 4 hours or less, 3.5 hours or less, 3 hours or less, 3.5 hours or less, 3 hours or less, 2.5 hours or less, 2 hours or less, 1.5 hours or less, 1 hour or less or 30 minutes or less.

In an exemplary embodiment of the present disclosure, the stirring in step (3) can be carried out at a temperature of 20°C or higher, 25°C or higher, 30°C or higher, 35°C or higher, 40°C or higher, 45°C or higher, 50°C or higher, 55°C or higher or 60°C or higher, or 70°C or lower, 65°C or lower, 60°C or lower, 55°C or lower, 50°C or lower, 45°C or lower, 40°C or lower, 35°C or lower, 30°C or lower, 25°C or lower or 20°C or lower.

In an exemplary embodiment of the present disclosure, the method may further include: (4) a step of cooling the mixture of step (3).

In an exemplary embodiment of the present disclosure, the method may further include: (5) obtaining a diastereomeric salt of the compound by filtering the obtained solid. Specifically, in an exemplary embodiment of the present disclosure, the diastereomeric salt of the compound may be a diastereomeric salt of INT-3.

In an exemplary embodiment of the present disclosure, the method may further include: (6) a step of removing or separating the chiral acid from the obtained diastereomeric salt.

In an exemplary embodiment of the present disclosure, step (6) may include: 1) the step of adding the diastereomeric salt of INT-3 to water and an aqueous ammonia solution. Specifically, in an exemplary embodiment of the present disclosure, based on the weight of the diastereomeric salt of INT-3, the amount of water in step (6) may be 2 times or more, 3 times or more, 4 times or more, 5 times or more, 6 times or more or 7 times or more, or 7 times or less, 6 times or less, 5 times or less, 4 times or less, 3 times or less or 2 times or less. Specifically, in an exemplary embodiment of the present disclosure, the aqueous ammonia solution in step (6) may be 20% by volume or more, 24% by volume or more, 28% by volume or more, 32% by volume or more, 36% by volume or more or 40% by volume or more of an aqueous ammonia solution, or 40% by volume or less, 36% by volume or less, 32% by volume or less, 28% by volume or less, 24% by volume or less or 20% by volume or less of an aqueous ammonia solution. Specifically, in an exemplary embodiment of the present disclosure, the amount of the aqueous ammonia solution in step (6) can be 0.5 equivalents or more, 1 equivalent or more, 1.5 equivalents or more, 2 equivalents or more, 2.5 equivalents or more or 3 equivalents or more, or 4 equivalents or less, 3.5 equivalents or less, 3 equivalents or less, 2.5 equivalents or less, 2 equivalents or less, 1.5 equivalents or less, 1 equivalent or less or 0.5 equivalents or less.

In an exemplary embodiment of the present disclosure, step (6) may further include, after step 1), the step of: 2) stirring the obtained mixture solution. Specifically, in an exemplary embodiment of the present disclosure, the stirring in step (6) may be performed for 5 minutes or longer, 10 minutes or longer, 20 minutes or longer, 30 minutes or longer, 40 minutes or longer, 50 minutes or longer, 60 minutes or longer, or 70 minutes or longer, or 70 minutes or shorter, 60 minutes or shorter, 50 minutes or shorter, 40 minutes or shorter, 30 minutes or shorter, 20 minutes or shorter, or 10 minutes or shorter.

In an exemplary embodiment of the present disclosure, step (6) may further include: 3) filtering the obtained suspension.

In an exemplary embodiment of the present disclosure, step (6) may further include: 4) a step of obtaining the R or S optical isomer of INT-3 by removing water from the filtered suspension (particularly under reduced pressure).

In another aspect, the present invention provides a method for preparing a compound of formula (IIIa) or (IIIb)

wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are each independently any one selected from H, -NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and halogen, and

_R1 and _R2 are different from each other, and the method comprises

Said stereoisomer mixture of the compound of formula (I) is resolved, in particular chirally resolved, according to the process of the present disclosure, and

The resulting stereoisomer is converted into a compound of formula (IIIa) or (IIIb). The conversion step is also described in detail in Korean Patent Application No. 10-2009-700433.

In an exemplary embodiment of the present disclosure, the compound of formula (IIIa) can be (R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide, and the compound of formula (I) can be N-{4-[(1R/S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide.

In another exemplary embodiment of the present disclosure, the converting step may include the step of coupling N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide (INT-3) with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (INT-7).

The R isomer compound resolved by the method according to the present disclosure can be reacted with the substance described in Korean Patent Application No. 10-2009-700433 to be used as an intermediate for preparing the novel drug described in the patent application. Therefore, in another aspect, the present disclosure relates to a method for preparing the novel drug described in Korean Patent Application No. 10-2009-700433, which uses the R isomer compound resolved by the method according to the present disclosure, or to a novel drug prepared by the method.

In an exemplary embodiment of the present disclosure, there is provided (R)-N-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide, which can be obtained by the method of the present disclosure with an enantiomeric excess of at least 96%, at least 97%, at least 98%, at least 99%, or between 96% and 99%.

In another aspect, the present disclosure provides a TRPV1 antagonist comprising (R)-N-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-3-(2-propyl-6-trifluoromethylpyridin-3-yl)-acrylamide (PAC-14028) prepared according to the method of the present disclosure as an active ingredient. The TRPV1 antagonist can be used in a pharmaceutical composition for preventing or treating the following diseases.

In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising (R)-N-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-3-(2-propyl-6-trifluoromethylpyridin-3-yl)-acrylamide, an optical isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for preventing or treating a disease associated with pathological stimulation and/or abnormal expression of a vanilloid receptor selected from the group consisting of pain, arthritis, neuropathy, HIV-related neuropathy , nerve damage, neurodegeneration, stroke, urinary incontinence, cystitis, gastric/duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurological/allergic/inflammatory skin diseases, psoriasis, itching, prurigo, skin irritation, eye or mucous membrane inflammation, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, myocardial ischemia, hirsutism, hair loss, alopecia, rhinitis and pancreatitis.

In an exemplary embodiment of this aspect of the disclosure, the pain can be a disease selected from or associated with a disease selected from osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, dental pain, fibromyalgia, myofascial pain syndrome, back pain, migraine and other types of headaches.

In another aspect, the present disclosure provides a composition comprising: a chiral auxiliary selected from one or more of 2,3-dibenzoyl-tartaric acid, O,O'-di-p-toluoyl-tartaric acid, stereoisomers thereof, and combinations thereof; and a salt-forming compound selected from one or more of mandelic acid, camphorsulfonic acid, stereoisomers thereof, and combinations thereof. In one aspect, the composition can be a chiral resolving composition or a chiral resolving agent.

In an exemplary embodiment of the composition according to the present invention, the molar equivalent ratio of the chiral auxiliary to 1 molar equivalent of the stereoisomer mixture to be resolved may be equal to or less than 0.5, or 0.15 to 0.5, 0.25 to 0.35 or 0.25.

In an exemplary embodiment of the composition according to the present invention, the molar equivalent ratio of the salt-forming compound to 1 molar equivalent of the stereoisomer mixture to be resolved may be 0.75 to 1.5.

In an exemplary embodiment of the present invention, the molar equivalent ratio of the salt-forming compound to 1 molar equivalent of the chiral auxiliary in the composition may be 1.5 to 6, specifically 3 to 6 (ie, 3 to 6 moles of the salt-forming compound per mole of the chiral auxiliary).

In another aspect, the present disclosure provides a composition comprising: a chiral auxiliary; and a salt-forming compound.

In an exemplary embodiment of the present disclosure, the composition may contain 0.10 to 0.5 equivalents of the chiral auxiliary per 1 equivalent of the stereoisomer mixture requiring chiral resolution.

In an exemplary embodiment of the present disclosure, the composition may contain 0.75 to 1.5 equivalents of the salt-forming compound per 1 equivalent of the stereoisomer mixture.

In another aspect, the present disclosure provides a resolution kit comprising a chiral auxiliary and a salt-forming compound.

In another aspect, the present disclosure provides a chiral resolution kit comprising: a chiral auxiliary selected from one or more of 2,3-dibenzoyl-tartaric acid, O,O′-di-p-toluoyl-tartaric acid, stereoisomers thereof, and combinations thereof; and a salt-forming compound selected from one or more of mandelic acid, camphorsulfonic acid, stereoisomers thereof, and combinations thereof.

In an exemplary embodiment of the present disclosure, the chiral resolution kit according to the present invention may further comprise written instructions for using the chiral auxiliary and the salt-forming compound, particularly for resolving a mixture of stereoisomers of the compound of formula (I).

In an exemplary embodiment of the present invention, the molar equivalent ratio of the chiral auxiliary to 1 equivalent of the stereoisomer mixture to be resolved may be equal to or less than 0.5, 0.15 to 0.5, 0.25 to 0.35, or 0.25.

In an exemplary embodiment of the present invention, the molar equivalent ratio of the salt-forming compound to 1 equivalent of the stereoisomer mixture to be resolved may be 0.75 to 1.5.

In an exemplary embodiment of the present disclosure, the kit according to the present invention may further comprise written instructions for using the chiral auxiliary and the salt-forming compound.

In an exemplary embodiment of the present disclosure, the written instructions may include a description that the chiral auxiliary is used in an amount of 0.10 to 0.5 equivalents per 1 equivalent of the mixture of stereoisomers to be chirally resolved.

In an exemplary embodiment of the present disclosure, the written instructions may include a description that the amount of the salt-forming compound to be used is 0.75 to 1.5 equivalents per 1 equivalent of the mixture of stereoisomers to be chirally resolved.

In an exemplary embodiment of the chiral resolution kit according to the present invention, the molar equivalent ratio of the salt-forming compound to 1 molar equivalent of the chiral auxiliary can be 1.5 to 6, specifically 3 to 6 (i.e., 3 to 6 moles of the salt-forming compound for each mole of the chiral auxiliary).

In an exemplary embodiment of the present disclosure, the written instructions can include instructions for combining the chiral auxiliary and the salt-forming compound with the stereoisomer mixture in a polar protic solvent.

In an exemplary embodiment of the present disclosure, the written instructions may include a description of the method described in the present disclosure for resolving a mixture of stereoisomers.

In another aspect, the present disclosure provides use of a composition or kit according to the present disclosure for chiral resolution of a mixture of stereoisomers.

Hereinafter, the present disclosure will be described in detail by the following examples. However, the following examples are only for illustrative purposes, and the scope of the present disclosure is not limited by these examples. In addition, it will be apparent to those of ordinary skill in the art that various changes and modifications may be made thereto without departing from the scope of the present disclosure.

[Comparative Test Example 11 Measurement of Optical Purity of Existing Asymmetric Synthesis Methods]

The asymmetric synthesis was carried out according to Scheme 2.

[Scheme 2]

N-{2,6-difluoro-4-[1-(2-methylpropane-2-sulfinylamino)-ethyl]-phenyl}-methanesulfonamide was dissolved by adding tetrahydrofuran (THF) (20 mL) in an amount 10 times the weight thereof. NaBH ₄ (4 equivalents) was further dissolved in the resulting solution, and the reaction was carried out at the temperature described in Table 1 for 10 hours. Then, CH ₃ OH was added dropwise until no hydrogen gas evolution was observed.

The mixture was concentrated under reduced pressure and then purified by chromatography to afford N-{2,6-difluoro-4-[1-(2-methylpropane-2-sulfinylamino)-ethyl]-phenyl}-methanesulfonamide. The mixture was stirred at room temperature for 30 minutes while an excess of 4M HCl in dioxane was added dropwise, then concentrated under reduced pressure. The resulting residue was purified by recrystallization from acetone to afford (R)-N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide hydrochloride.

The enantiomeric excess (ee %) of the obtained salt was measured in the same manner as in the Test Example. The results are shown in Table 1.

[Table 1]

Comparative Example ee% (R isomer) 1-1 -48 96.2 1-2 -30 95.4 1-3 -20 95.2 1-4 -10 94.9 1-5 0 94.2

As can be seen from Table 1, in order to achieve an optical activity of 96% or higher using existing methods, the temperature must be continuously maintained below -40°C for 10 hours. However, according to the present disclosure, the same optical activity can be achieved by stirring and purifying at 50°C. Therefore, it can be seen that the method of the present disclosure is very economical compared to existing methods. If the reaction is scaled up to a factory scale, maintaining the temperature at 50°C for 10 hours is easier than maintaining the temperature at -40°C for 10 hours. Therefore, the reaction scale of the method of the present disclosure can be more easily scaled up compared to existing methods.

Furthermore, existing methods using 2 to 4 equivalents of sodium borohydride are very dangerous due to the excessive production of explosive hydrogen and the generation of heat during the reaction. In contrast, the method of the present disclosure makes it possible to prepare commercially useful stereoisomers having an optical activity of 96% or more without involving the excessive production of explosive hydrogen or heat.

In summary, the method of the present disclosure is more economical and safer than existing methods.

[Comparative Test Example 2] Measurement of Optical Purity of Resolution Using a Chiral Resolving Agent

N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide (a mixture of R and S stereoisomers) was prepared according to the preparation method described in Bioorganic & Medicinal Chemistry 15(18), 6043-6053; 2007. One equivalent of the prepared N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide was mixed with one equivalent of the chiral auxiliary described in Tables 2 and 3. To the resulting mixture was added 10 times (by volume) of a solvent (different solvents as described in the table) based on the weight of N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide. The resulting mixture solution was refluxed at 50° C. for 3 hours and then cooled to 25° C. The resulting solid was filtered using a Buchner funnel to obtain each N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide chiral acid salt. The salt obtained was a once-resolved salt.

To the obtained once-resolved N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide salt, ten times the weight of the solvent was added, and then the above-mentioned reflux procedure was performed once and twice, cooled and then filtered to obtain twice-resolved and three-resolved N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide salt.

To each obtained N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide chiral acid salt was added 5 times of water based on its weight and 2 equivalents of 28% by volume ammonia solution, and the mixture was stirred for 30 minutes. The resulting suspension was filtered using a Buchner funnel, and excess water was removed under reduced pressure to give N-[4-(1R)-1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide or N-[4-[(1S)-1-aminoethyl]-2,6-difluorophenyl]-methanesulfonamide (INT-3).

The optical purity (enantiomeric excess) of the obtained INT-3 was analyzed using a chiral HPLC column (Shiseido Chiral CD-Ph, 4.6 mm × 250 mm, 5 μm). A mixed solution of 0.5 mol/L sodium perchlorate and methanol (75% by volume: 25% by volume) was used as the mobile phase, and the optical purity (enantiomeric excess, ee%) of each chiral acid salt was measured using a Waters e2695 Alliance HPLC system and calculated according to Equation 1. In addition, the yield of the reaction was calculated according to Equation 2. Only the yield of the three-fold resolved salt with the highest optical activity was calculated.

The results are shown in Tables 2 and 3.

<HPLC conditions>

1. Column temperature = 35°C

2. Flow rate = 0.5 mL/min

3. Detection wavelength = 220nm

4. R _t (min) = 20.4 (R-enantiomer%), 18.9 (S-enantiomer%)

[Equation 1]

[Equation 2]

Actual output: the amount of product obtained.

Theoretical yield: the maximum amount of product that can be obtained from a given amount of reactants

[Table 2]

[Table 3]

As can be seen from Tables 2 and 3, when only dibenzoyltartaric acid or ditoluoyltartaric acid is used, higher purity of the optical isomers can be obtained as the number of resolutions increases. In particular, the purity is highest when methanol or ethanol is used. However, when the number of resolutions is less than three, the purity is very low compared to the commercially useful purity of at least 96% ee.

Furthermore, when only dibenzoyltartaric acid or ditoluoyltartaric acid is used, the isomer yield is very low, for example, less than 20%, regardless of the solvent.

[Test Example 1] Optical Purity Measurement of Different Chiral Auxiliaries and Auxiliary Salt-Forming Compounds and Their Mixing Ratios

N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide (stereoisomer mixture of R and S isomers) was prepared according to the preparation method described in Bioorganic & Medicinal Chemistry 15(18), 6043-6053; 2007. One equivalent of the prepared N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide was mixed with the chiral auxiliary and auxiliary salt-forming compound described in Tables 4 to 8 in equivalent amounts. To the resulting mixture was added a solvent (different solvents as described in Tables 4 to 8) in an amount 10 times the weight of the methanesulfonamide compound. The resulting mixture solution was refluxed at 50° C. for 3 hours and then cooled to 25° C. The resulting solid was filtered using a Buchner funnel to obtain each INT-3 chiral acid salt.

To each obtained N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide chiral acid salt was added 5 times of water based on its weight and 2 equivalents of 28% by volume ammonia solution, and the mixture was stirred for 30 minutes. The resulting suspension was filtered using a Buchner funnel, and excess water was removed under reduced pressure to give N-[4-(1R)-1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide or N-[4-(1S)-1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide (INT-3).

The optical purity (enantiomeric excess) of the obtained INT-3 was analyzed using a chiral HPLC column (Shiseido Chiral CD-Ph, 4.6 mm × 250 mm, 5 μm). A mixed solution of 0.5 mol/L sodium perchlorate and methanol (75% by volume: 25% by volume) was used as the mobile phase, and the optical purity (enantiomeric excess, ee%) of each chiral acid salt was measured using a Waters e2695 Alliance HPLC system.

The results are shown in Tables 4-8. Table 4 shows such test results. Both the optical purity and the yield of INT-3 are affected by the optical activity of mandelic acid, which is one of the auxiliary salt-forming compounds. Table 5 shows the results when 2,3-dibenzoyltartaric acid and mandelic acid are used. Table 6 shows the results when 2,3-dibenzoyltartaric acid and camphorsulfonic acid are used. Table 7 shows the results when di-p-toluoyltartaric acid and mandelic acid are used. Table 8 shows the results when ditoluoyltartaric acid and camphorsulfonic acid are used. Each table shows the results of obtaining chiral acid salts using different solvents.

<HPLC conditions>

1. Column temperature = 35°C

2. Flow rate = 0.5 mL/min

3. Detection wavelength = 220nm

4. R _t (min) = 20.4 (R-enantiomer%), 18.9 (S-enantiomer%)

The optical purity was calculated according to Equation 1, and the yield of the reaction was calculated according to Equation 2.

Camphorsulfonic acid, mandelic acid, 2,3-dibenzoyltartaric acid and O,O'-di-p-toluoyltartaric acid used in the experiments were purchased from Sigma Aldrich.

[Table 4]

[Table 5]

For mandelic acid, the D and L isomers gave identical results.

[Table 6]

For camphorsulfonic acid, the R and S isomers gave identical results.

[Table 7]

For mandelic acid, the D and L isomers gave identical results.

[Table 8]

For camphorsulfonic acid, the R and S isomers gave identical results.

As can be seen from Table 4, the optical activity of mandelic acid, a soluble salt-forming compound, does not affect optical resolution. Specifically, when D or L mandelic acid or a mixture thereof is used, almost identical results are obtained. Therefore, it can be seen that tartaric acid derivatives such as dibenzoyltartaric acid play an important role in optical resolution.

As can be seen from Tables 5 to 8, when diacyltartaric acid is used for optical resolution, 2 equivalents (molecules) of N-[4-(1-aminoethyl)-phenyl]-methanesulfonamide and 1 equivalent (molecule) of diacyltartaric acid are reacted in a polar solvent such as water, methanol, ethanol and isopropanol to form a salt, as described in Scheme 1.

Furthermore, it can be seen from Tables 5 to 8 that for a given equivalent of mandelic acid and camphorsulfonic acid, when diacyltartaric acid is used in amounts of 0.25 equivalent, 0.35 equivalent, 0.5 equivalent, and 1 equivalent, the optical purity is highest when 0.25 equivalent is used, followed by 0.35 equivalent and 0.5 equivalent. When 1 equivalent of diacyltartaric acid is used, the optical purity is very low.

Thus, it can be seen that in polar solvents such as water, methanol, ethanol and isopropanol, 2 equivalents (molecules) of N-[4-(1-aminoethyl)-phenyl]-methanesulfonamide and 1 equivalent (molecule) of diacyltartaric acid form selectively resolvable salts.

Specifically, with reference to Tables 5 and 6 in which 2,3-dibenzoyl-D-tartaric acid and mandelic acid or camphorsulfonic acid are used, when water is used as a solvent, the optical purity is as low as 89% ee or lower. When methanol or ethanol is used, when 0.25 equivalent or 0.35 equivalent of tartaric acid is used, the optical purity is 96% ee or higher, but the yield is 25% or lower. However, compared to when only 2,3-dibenzoyl-D-tartaric acid is used, the yield is 2 times or higher (see Table 2). In particular, when the solvent is methanol and mandelic acid, no splitting occurs when 0.5 equivalent of dibenzoyl-D-tartaric acid is used, but splitting occurs when camphorsulfonic acid is used. When the solvent is isopropyl alcohol, when 0.25 equivalent, 0.35 equivalent or 0.5 equivalent of tartaric acid is used, an optical purity of 96% ee or higher can be obtained, and the yield is also 20% or higher. In particular, when 0.25 equivalent or 0.35 equivalent of tartaric acid was used, the yield was 40% or more.

Based on these results, experiments were conducted in isopropanol while varying the equivalents of mandelic acid or camphorsulfonic acid while maintaining the same tartaric acid equivalent (Examples 2-17 to 2-22 and Examples 3-17 to 3-22). Thus, when 0.5 equivalents or less of tartaric acid was used, and when 0.75 to 1.5 equivalents of mandelic acid or camphorsulfonic acid was used, the R isomer with a high optical purity of 96% ee or higher and a high yield was obtained. In particular, an isomer with a high optical purity of 96% ee or higher was obtained, and the highest yield of 42% was achieved in Example 2-17.

With reference to Tables 7 and 8 in which O, O'-di-p-toluoyltartaric acid and mandelic acid or camphorsulfonic acid are used, when water is used as a solvent, the optical purity is as low as 80%ee or lower. When methanol or ethanol is used, when 0.25 equivalent or 0.35 equivalent of tartaric acid is used, the optical purity is 96%ee or higher, but the yield is 25% or lower. However, compared to when only O, O'-di-p-toluoyltartaric acid is used (see Table 3), the yield is 2 times or higher. In addition, when camphorsulfonic acid is used, when 0.5 equivalent of di-p-toluoyltartaric acid is used, optical resolution occurs in methanol. When the solvent is isopropanol, when 0.25 equivalent, 0.35 equivalent or 0.5 equivalent of tartaric acid is used, an optical purity of 96%ee or higher can be obtained, and the yield is also 20% or higher. In particular, when 0.25 equivalent or 0.35 equivalent of tartaric acid was used, the yield was 34% or more.

In Examples 4-17 to 4-22 and 5-17 to 5-22, experiments were conducted in isopropanol, with the equivalents of tartaric acid held constant while varying the equivalents of mandelic acid or camphorsulfonic acid. Thus, when 0.5 equivalents or less of tartaric acid was used, and when 0.75 to 1.5 equivalents of mandelic acid or camphorsulfonic acid was used, the R isomer was obtained with a high optical purity of 96% ee or higher and in high yields. In particular, the isomer was obtained with a high optical purity of 96% ee or higher, and the highest yield of 40% was achieved in Example 4-17.

In summary, when using 0.25 to 0.5 equivalents of diacyltartaric acid and 0.75 to 1.5 equivalents of mandelic acid or camphorsulfonic acid, the R isomer can be obtained with a high optical purity of 96% ee or higher. In particular, when the solvent is isopropanol, the isomer can be obtained in a higher yield. Furthermore, when the solvent is isopropanol, by using 0.25 to 0.35 equivalents of diacyltartaric acid and 0.75 to 1.5 equivalents of mandelic acid or camphorsulfonic acid, the isomer can be obtained with a high optical purity of 96% ee or higher in a yield of 30% or higher.

It is obvious to those skilled in the art that when 2,3-dibenzoyltartaric acid or O,O'-di-p-benzoyltartaric acid is the L isomer, N-{4-[(1S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide will be obtained.

Therefore, the R or S optical isomer can be obtained with high optical purity by the method according to the present disclosure.

[Test Example 2] Preparation of (R)-N-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-3-(2-propyl-6-trifluoromethylpyridin-3-yl)-acrylamide

According to the method described in Korean Patent Application No. 10-2009-700433, (R)-N-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-3-(2-propyl-6-trifluoromethylpyridin-3-yl)-acrylamide was prepared using N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide prepared according to the present disclosure.

Specifically, N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide hydrochloride (62 mg, 0.22 mmol) was reacted with 3-(2-propyl-6-trifluoromethylpyridin-3-yl)-acrylic acid (56 mg, 0.22 mmol). The product was purified by crystallization from diethyl ether to obtain the target compound (81 mg, 73%).

¹ H NMR (300MHz, DMSO-d ₆ ): δ9.50 (bs, 1H), 8.81 (d, 1H, J = 7.8Hz), 8.16 (d, 1H, J = 8.4Hz), 7.80 (d, 1H, J = 7.8Hz), 7.67 (d, 1H, J = 15.6Hz), 7.18 (d, 2H, J = 7. 2Hz), 6.76 (d, 1H, J=15.6Hz), 5.04 (m, 1H), 3.05 (s, 3H), 2.91 (m, 2H), 1.65 (m, 2H), 1.41 (d, 3H, J=6.9Hz), 0.92 (t, 3H, J=7.2Hz).

ESI[M+H] ⁺ ：492

Therefore, the R isomer of the compound having the structure of formula (I) that has been resolved by the method according to the present disclosure can be used as an intermediate to prepare various novel compounds that can act as TRPV1 antagonists using the methods or materials described in Korean Patent Application No. 10-2009-700433.

Hereinafter, the formulation examples of the composition according to the present disclosure will be described. However, the following examples are for illustrative purposes only, and it is obvious to those skilled in the art that the scope of the present disclosure is not limited by the examples.

[Preparation Example 1] Amorphous Chiral Resolving Agent Composition

The amorphous solid chiral resolving agent comprises, for every 1 equivalent of the mixture of stereoisomers, 0.15 to 0.5 equivalents of at least one of 2,3-dibenzoyltartaric acid and O,O'-di-p-toluoyltartaric acid; and 0.75 to 1.5 equivalents of at least one of mandelic acid and camphorsulfonic acid.

[Preparation Example 2] Crystalline Chiral Resolving Agent Composition

The crystalline solid chiral resolving agent comprises, for every 1 equivalent of the mixture of stereoisomers, 0.15 to 0.5 equivalents of at least one of 2,3-dibenzoyltartaric acid and O,O'-di-p-toluoyltartaric acid; and 0.75 to 1.5 equivalents of at least one of mandelic acid and camphorsulfonic acid.

Claims (29)

1. A chiral resolution method for a mixture of stereoisomers of compound (I), _R1 , _R2 , _R3 , _R4 , _R5 , _R6 , and _R7 are each independently selected from H, _-NH2 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, and halogen, and _R1 and R2 are different from each other. The method comprises mixing the mixture of stereoisomers of the compound of formula (I) with the following substances in the presence of a solvent: (i) chiral auxiliaries; and (ii) Auxiliary salt-forming compounds This causes the chiral auxiliary agent (i) and the diastereomeric salt of the compound of formula (I) to precipitate enantiomeric excess. The chiral auxiliary agent is selected from one or more of 2,3-dibenzoyl tartaric acid, O,O′-di-p-toluamide tartaric acid, their stereoisomers, and combinations thereof. The auxiliary salt-forming compound is selected from one or more of mandelic acid, camphor sulfonic acid, their stereoisomers, and combinations thereof, and The molar equivalent ratio of the chiral auxiliary to 1 molar equivalent of the stereoisomer mixture is from 0.01 to 0.45. 2. The method according to claim 1, wherein R ₂ is hydrogen, and when the chiral auxiliary is selected from (+)-2,3-dibenzoyl-D-tartaric acid, (+)-O,O′-di-p-toluyl-D-tartaric acid and combinations thereof, the R enantiomer of the compound of formula (I) is obtained in enantiomer excess. 3. The method according to claim 1, wherein _R2 is hydrogen, and when the chiral auxiliary is selected from (-)-2,3-dibenzoyl-L-tartaric acid, (-)-O,O′-di-p-toluyl-L-tartaric acid and combinations thereof, the S enantiomer of the compound of formula (I) is obtained in enantiomer excess. 4. The method according to claim 1, wherein the auxiliary salt-forming compound is D-mandelic acid, L-mandelic acid, (1R)-(-)-10-camphorsulfonic acid, (1S)-(+)-10-camphorsulfonic acid, or a combination thereof. 5. The method according to claim 1, wherein the halogen is selected from one or more of F, Cl, Br and I. 6. The method according to claim 5, wherein _R1 is selected from methyl, ethyl, propyl, butyl, and pentyl, and _R2 is hydrogen. 7. The method according to claim 6, wherein _R1 is methyl, _R2 , _R3 and _R7 are hydrogen, and _R4 , _R5 and _R6 are independently selected from F, C1, methyl, ethyl and propyl. 8. The method according to claim 7, wherein the compound of formula (I) is N-{4-[(1R/S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide. 9. The method according to claim 1, wherein the solvent is one or more selected from water, _C1-14 alcohol, acetic acid, nitromethane, propionic acid, formic acid, and combinations thereof. 10. The method of claim 9, wherein the solvent is one or more selected from water, methanol, ethanol and isopropanol. 11. The method of claim 10, wherein the solvent is methanol, isopropanol, or a combination thereof. 12. The method of claim 1, wherein the solvent is added in an amount sufficient to achieve complete dissolution of all reactants. 13. The method of claim 12, wherein the solvent is added in an amount of 5 to 15 times (volume/weight) of the total weight of the stereoisomer mixture based on formula (I). 14. The method of claim 1, wherein the mixing is carried out at a temperature of 40°C to 70°C or at the boiling point of the solvent or solvent mixture. 15. The method according to any one of claims 1 to 14, wherein the molar equivalent ratio of the chiral auxiliary to 1 molar equivalent of the stereoisomer mixture is 0.10 to 0.45. 16. The method of claim 15, wherein the molar equivalent ratio of the chiral auxiliary to 1 molar equivalent of the stereoisomer mixture is 0.2 to 0.3. 17. The method according to any one of claims 1 to 14, wherein the molar equivalent ratio of the auxiliary salt-forming compound to 1 molar equivalent of the stereoisomer mixture is 0.5 to 1.5. 18. The method of claim 17, wherein the molar equivalent ratio of the auxiliary salt-forming compound to 1 molar equivalent of the stereoisomer mixture is from 0.75 to 1.5. 19. The method according to any one of claims 1 to 14, wherein the molar equivalent ratio of the chiral auxiliary agent and the auxiliary salt-forming compound together with 1 molar equivalent of the stereoisomer mixture is 0.75 to 2.0. 20. Methods for preparing compounds of formula (IIIa) or (IIIb) _R1 , _R2 , _R3 , _R4 , _R5 , _R6 , and _R7 are each independently selected from H, _-NH2 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, and halogen, and _R1 and _R2 are different from each other. The method includes: The mixture of stereoisomers of the compound of formula (I) as described in any one of claims 1 to 15, and The resulting stereoisomers were converted into compounds of formula (IIIa) or (IIIb). 21. The method according to claim 20, wherein the compound of formula (IIIa) is (R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide, and the compound of formula (I) is N-{4-[(1R/S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide. 22. The method of claim 20, wherein converting the resulting stereoisomer into a compound of formula (IIIa) or (IIIb) comprises coupling N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide (INT-3) with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)acrylic acid (INT-7). 23. Use of chiral auxiliaries and auxiliary salt-forming compounds in the manufacture of compositions for resolving mixtures of stereoisomers of compound (I), _R1 , _R2 , _R3 , _R4 , _R5 , _R6 , and _R7 are each independently selected from H, _-NH2 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, and halogen, and _R1 and _R2 are different from each other. The chiral auxiliary agent is selected from one or more of 2,3-dibenzoyl-tartaric acid, O,O′-di-p-toluyl-tartaric acid, their stereoisomers, and combinations thereof, and the auxiliary salt-forming compound is selected from one or more of mandelic acid, camphor sulfonic acid, their stereoisomers, and combinations thereof. The molar equivalent ratio of the chiral auxiliary to 1 molar equivalent of the stereoisomer mixture is from 0.01 to 0.45. 24. The use according to claim 23, wherein the composition comprises 0.10 to 0.45 molar equivalents of a chiral auxiliary agent based on a 1 molar equivalent mixture of stereoisomers to be separated. 25. The use according to claim 23, wherein, based on a 1 molar equivalent of the stereoisomer mixture to be resolved, the composition comprises 0.75 to 1.5 molar equivalents of an auxiliary salt-forming compound. 26. Use of chiral auxiliaries and auxiliary salt-forming compounds in the manufacture of a chiral resolution kit, the chiral resolution kit comprising: a chiral auxiliaries selected from one or more of 2,3-dibenzoyl-tartaric acid, O,O′-di-p-toluyl-tartaric acid, their stereoisomers, and combinations thereof; and an auxiliary salt-forming compound selected from one or more of mandelic acid, camphor sulfonic acid, their stereoisomers, or combinations thereof. The molar equivalent ratio of the chiral auxiliary to the 1 molar equivalent of the stereoisomer mixture is from 0.01 to 0.45, and The kit described herein is used to resolve mixtures of stereoisomers of compound (I). _R1 , _R2 , _R3 , _R4 , _R5 , _R6 and _R7 are each independently selected from H, _-NH2 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl and halogen, and _R1 and _R2 are different from each other. 27. The use according to claim 26, wherein the molar equivalent ratio of the chiral auxiliary to a 1 molar equivalent mixture of stereoisomers to be separated is from 0.10 to 0.45. 28. The use according to claim 26, wherein the molar equivalent ratio of the auxiliary salt-forming compound to a 1 molar equivalent mixture of stereoisomers to be resolved is 0.75 to 1.5. 29. The use according to claim 26, wherein the kit further comprises written instructions for using the chiral auxiliaries and the auxiliary salt-forming compounds to resolve the mixture of stereoisomers.